Lino Furlani - Associazione Medici...

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Lino Furlani Servizio di Endocrinologia Ospedale “Sacro Cuore – Don Calabria” Negrar - Verona

Transcript of Lino Furlani - Associazione Medici...

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Lino Furlani

Servizio di Endocrinologia Ospedale

“Sacro Cuore – Don Calabria” Negrar - Verona

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Gruppo di neoplasie eterogeneo

•  Relativamente raro riscontro •  Generalmente a crescita lenta

(varianti aggressive) •  varietà di presentazione

clinica •  sintomi vaghi ed aspecifici •  Ritardo di 5 – 7 anni nella

diagnosi: > 60% in progressione alla diagnosi

•  Terminologia e classificazioni non univoche

•  Diagnosi istologica difficile

Esofago

Mammella

Stomaco

Pancreas

Div.lo di Meckel Retto

Ovaia/Utero Prostata

Appendice

Colon

Intestino tenue

Vie Biliari

Fegato

Polmone

GEP-NET

ALTRI NET

TUMORI NEUROENDOCRINI Canine Family: Heterogeniety

Un efficace approccio terapeutico presuppone un corretto inquadramento clinico e una diagnosi precoce

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Quando sospettarne la presenza ???

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TUMORI ENDOCRINI del TRATTO GATROINTESTINALE

•  GEP originano per la maggior parte dal pancreas

•  Presentano generalmente crescita lenta •  Non particolarmente aggressivi anche quando

metastatizzano

•  La loro presentazione clinica è tipicamente attribuibile alla loro competenza secretoria ormonale

Principles and Practice of Endocrinology and Metabolism. Ed. Becker 1995

X X X

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NET

NET Bronchiali / Timo ! 25 % GEP-NET ! 67 %

Funzionanti

Non funzionanti

NET Bronchiali / Timo < 3% ACTH; più rari GHRH / ADH Sdr Carcinoide (metastasi)

> 97%

GEP-NET 20 % 80 % •  GEP-NET INTESTINO (70 %) 30 % 70 %

•  GEP-NET PANCREAS (30 %) 40 – 55 %

Gastrinoma Insulinoma Glucagonoma VIPoma Ppoma SSToma CRHoma GRFoma PTHRP

45 – 60%

Altri NET ! 8 %

Öberg K et al. Annals of Oncology (23): 2012

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Sindrome   Sostanza  iperespressa   Sede  del  tumore   Sintomo  

Sindrome  da  carcinoide  2pico  

Serotonina,  tachichinine,  bradichinine  e  prostaglandine   Pancreas,  ileo  e  polmone   Flushing  "6pico",  diarrea,  cardiopa6e,  

wheezing,  pellagra,  artri6  e  nefri6  

Sindrome  da  carcinoide  a2pico  

Istamina,  gastrina,  adrenalina  e,  raramente,  ormone  s6molante  i  melanoci6,  ormone  adrenocor6cotropo  e  poli-­‐pep6de  pancrea6co  

Stomaco  e  polmone  

Flushing  "a6pico",  diarrea,  cefalea,  scialo-­‐  e  rinorrea,  lacrimazione,  sudorazione  e  reazione  or6carioide  pruriginosa  

Sindrome  di  Zollinger-­‐Ellison  

Gastrina  e,  raramente,  ormone  adrenocor6cotropo,  polipep6de  pancrea6co  e  pep6de  intes6nale  vasoa?vo  

Pancreas,  duodeno  e  retroperitoneo  

Dispepsia  ulcerosa,  diarrea,  anemia,  e  steatorrea  

Sindrome  di  Verner-­‐Morrison  

Pep6de  intes6nale  vasoa?vo  e  polipep6de  pancrea6co   Pancreas  e  retroperitoneo  

Diarrea  acquosa,  ipocloridria,  ipopotassiemia,  ipercalcemia,  flushing  ed  acidosi  metabolica  

Sindrome  di  Cushing  Ormone  adrenocor6cotropo  ed  ormone  rilasciante  l'ormone  adrenocor6cotropo  

Surrene,  polmone,  2mo  e  pancreas  

Ipercor6solemia,  ipertensione  arteriosa.  Obesità  centrale  

Sindromi  da  crisi  ipoglicemiche  

Insulina  e,  raramente,  polipep6de  pancrea6co  e  pep6de  intes6nale  vasoa?vo  

Pancreas  (a)  segni  e  sintomi  di  ipoglicemia;  b)  glicemia  concomitante  (<  45  mg/dl);  c)  regressione  dei  sintomi  dopo  somministrazione  di  zuccheri;  

Sindromi  da  crisi  iperglicemiche  

Enteroglucagone   Colon,  re=o  ed  appendice   Iperglicemia  e  malassorbimento  intes6nale  

Sindrome  di  Becker  Glucagone  e,  raramente,  calcitonina,  insulina,  polipep6de  pancrea6co  e  somatosta6na  

Pancreas  Eritema  necroli6co  migrante,  diarrea,  diabete  mellito,  anemia,  stoma6te  angolare,  cheilite,  glossite  atrofica  e  porpora  

Ricerca genetica •  Sdr MEN •  VON HIPPEL LINDAU •  Paraganglioma / Feocromocitoma

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M  Modlin  et  al.  Clinical  update,  193:  46-­‐-­‐52,  2010  

•  FLUSHING  (80%)  •  rash  cutaneo  eritematoso  al  volto  e  collo  

dura  pochi  minu6;  scatenato  dall’inges6one  di  alcuni  cibi  (es.  ananas,  kiwi,  banane,  banane,  pomodori,  cioccolato),  bevande  alcooliche,  farmaci,  situazioni  di  stress  

 •  DIARREA  (75%)    

•  di  solito  post-­‐prandiale,  non  acquosa  

•  DOLORE  ADDOMINALE  (40%)  •  CARDIOPATIA  DA  CARCINOIDE  (40%)  •  TELEANGIECTASIE  AL  VOLTO  (25%)  •  BRONCOSPASMO  (25%)  •  SUDORAZIONE  PROFUSA  (15%)  •  LESIONI  CUTANEE  PELLAGRA  SIMILI  (5%)  

Sdr  da  CARCINOIDE    

   

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Fibrosi  endocardica  valvolare:    (Causata  degli  aumenta6  livelli  di  serotonina  che  s6molano    la  proliferazione  e  la  deposizione  di  collagene  da  parte  dei  fibroblas6)    

•  fissazione  e  retrazione  dei  lembi  valvolari  

•  disfunzione  valvolare  •  insufficienza  cardiaca  

•  Interessa  il  cuore  destro  (la  Serotonina  viene  ina?vata  a  livello  del    circolo  polmonare)  

•  una    delle  cause  maggiori  di  morbidità  e  mortalità  

CARDIOPATIA  da  CARCINOIDE  

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NET <> CARCINOIDE ?

Oberndorfer coined the term “karzinoide” in 1907 •  This term implies that these tumours are benign;

this is an unfortunate misnomer for the majority of NET

•  NET have malignant potential and metastasize, generally to the liver

Klöppel G, et al. Endocr Pathol. 2007;18:141-144. Bhattacharyya S, et al. Nat Rev Clin Oncol. 2009;6:429-433.

•  Referring to any NET, the term “carcinoid” should only be used in reference to carcinoid syndrome

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NET  “FUNZIONANTI”    

   

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•  Istologia indistinguibile

•  Immunocitochimica positiva per CgA e Sinaptofisina

•  Tasso di crescita ed evoluzione metastatica per entrambi correlata al «grading» (mitosi rate) (Ki67) e allo «staging» (TNM)

•  Presenza di recettori per la SMS

•  Aspetto analogo all’Imaging (radiologico, ecografico, medico-nucleare)

•  Analoga risposta ai trattamenti farmacologici, chirurgici e radioterapici

I NENs non funzionanti devono essere gestiti in modo identico ai NENs sintomatici. La distinzione “NENs funzionante o non funzionante” è un concetto clinico arcaico che dovrebbe essere scartato poiché i tumori sono indistinguibili a livello cellulare, biologico e morfologico. Tutte le evidenze attuali indicano che la loro diagnosi e il trattamento deve seguire gli stessi principi comuni.

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"  Più  spesso  di  riscontro  “incidentale”  

"  Diagnosi  tardiva  !  metastasi  

"  Sintomi  “aspecifici”  

#  PANCREAS  (testa)  o  Addominalgie  o  Anoressia,  nausea  o  I^ero  

#  INTESTINO  TENUE  o  Dolori  addominali  intermi^en6  o  Addome  acuto  (stozzamento  /  torsione  di  ansa  intes6nale)  o  Appendicite  

#  COLON  –  RETTO  o  Ematochezia,  S6psi  o  Dimagramento  o  Dolore  /  prurito  nella  regione  anale  

NET  “NON  FUNZIONANTI”  

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NET: steps diagnostici

1.  NET vs nonNET ! morfologia & NE markers

2.  NET vs NEC ! struttura + grade

3.  Grade 1 – 2 – 3 ! mitosi & Ki 67

4.  TNM Stage I-II-III-IV ! dimensioni & invasione

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Come arriva a noi il paziente ?

•  SINTOMI sospetti per una SINDROME

•  SINTOMI “ASPECIFICI”

•  RISCONTRO INCIDENTALE

•  QUALCUNO ha chiesto la determinazione di …..

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Come arriva a noi il paziente ?

•  SINTOMI sospetti per una SINDROME

•  SINTOMI “ASPECIFICI”

•  RISCONTRO INCIDENTALE

•  QUALCUNO ha chiesto la determinazione di …..

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Caso clinico •  Maria,  anni  79  •  DIABETE  6po  2.  GASTRITE  con  RGE;  DIVERTICOLOSI  del  Colon;  IPERCOLESTEROLEMIA;  

IPOTIROIDISMO  postchirurgico  •  Terapia:  Meeormina,  Simvasta6na,  L-­‐Tiroxina,  Pantoprazolo,  Aspirina,  Rifaximina  a  cicli,  

Clebopride  •  Anamnesi  specifica  

•  Nel  2012  riscontro  incidentale  di  Gozzo  plurinodulare  all'ECD  -­‐  TSA.  Tiroidectomia  Totale.    

•  Dal  2010  riferisce  crisi  di  alvo  “sciolto”  a  risoluzione  spontanea  d'inverno.  Ripresa  nell'estate  del  2011  e  così  nel  2012  ma  nel  2013  le  crisi  si  accentuano  con  scariche  liquide  3  -­‐  5  volte  al  giorno  associate  a  crisi  di  sudorazione.  Dimagramento  di  6  Kg  in  8  mesi  

PET-TC 68 Gallio DOTATOC

CROMOGRANINA “A”: 187,7 mcg/L (vn se < 84 mcg/L)

negativa

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Caso clinico •  Maria,  anni  79  •  DIABETE  6po  2.  GASTRITE  con  RGE;  DIVERTICOLOSI  del  Colon;  IPERCOLESTEROLEMIA;  

IPOTIROIDISMO  postchirurgico  •  Terapia:  Meeormina,  Simvasta6na,  L-­‐Tiroxina,  Pantoprazolo,  Aspirina,  Rifaximina  a  cicli,  

Clebopride,    

•  Sospeso  Clebopride  (MOTILEX®)  la  sintomatologia  è  ne^amente  migliorata:  ora  una  sola  scarica  alvina  al  giorno  di  feci  ancora  ben  formate.  Non  più  crisi  di  sudorazione.  

•  Sospeso  PANTOPRAZOLO  per  20  giorni  

CROMOGRANINA “A”: 33,4 mcg/L (vn se < 84 mcg/L)

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Chromogranin A as a marker ofneuroendocrine neoplasia: an ItalianMulticenter Study

Maria Chiara Zatelli, Mirella Torta1, Antonette Leon2, Maria Rosaria Ambrosio,Massimo Gion3, Paola Tomassetti 4, Filippo De Braud5, Gianfranco Delle Fave6,Luigi Dogliotti1, Ettore C degli Uberti, On behalf of the Italian CromaNet WorkingGroup

Section of Endocrinology, Department of Biomedical Sciences and Advanced Therapies, University of Ferrara, Via Savonarola 9,44100 Ferrara, Italy1Medical Oncology Unit, University of Torino at S. Luigi Hospital, Orbassano, Torino, Italy2ABO Association c/o Regional Centre for the Study of Biological Markers of Malignancy, General Regional Hospital, Venezia, Italy3Regional Centre for the Study of Biological Markers of Malignancy, General Regional Hospital, Venezia, Italy4Department of Internal Medicine and Gastroenterology, University of Bologna, Bologna, Italy5Unit of Clinical Pharmacology and New Drugs, European Institute of Oncology (IEO), Milano, Italy6Department of Gastroenterology, University of Rome at S. Andrea Hospital, Roma, Italy

(Requests for offprints should be addressed to E C degli Uberti; Email: [email protected])

Abstract

ElevatedcirculatingchromograninA (CgA) levelsare found inneuroendocrine tumors (NETs), but thediagnostic usefulness of this marker is still debatable. To assess the role of CgA for the diagnosis ofgastroenteropancreatic (GEP) NETs and the identification of metastatic patients, an Italianmulticenter observational study has been performed. CgA was evaluated in 202 GEP NET patientsby IRMA and ELISA. The cutoffs for diagnosis and presence of metastases were identified byreceiver-operating characteristic (ROC)curve.We foundgoodcorrelationbetween IRMAandELISA.The ROC analysis identified a cutoff of 53 ng/ml for IRMA and 16 U/l for ELISA as discriminatingbetween controls and patients with active disease (sensitivity 71.3 and 84%; specificity 71 and 85%respectively). Metastases were present in 123 patients, having significantly higher CgA levels thanpatients without metastases. ROC analysis identified a cutoff of 146 ng/ml for IRMA and 67.3 U/l forELISA as discriminating between patients with and without metastases (sensitivity 57 and 63.3%;specificity 55.6 and 71.4% respectively). For pancreatic NETs positive and negative predictivevalues were 84 and 78% respectively (90% specificity and 68% sensitivity). We found lower CgAlevels in patients with extensive metastatic spread than in those with liver metastases only. Thesedata assess the role of CgA evaluation in GEP NETs, and demonstrate that higher CgA levelsassociate with metastatic disease, confirming that CgA levels can provide a helpful practicalbiochemical marker for the clinical management of NETs, but with low sensitivity and specificity.

Endocrine-Related Cancer (2007) 14 473–482

Introduction

Chromogranin A (CgA) is an acidic glycoproteinexpressed in the secretory granules of most normal andneoplastic neuroendocrine (NE) cell types, where it isreleased together with peptide hormones and biogenicamines (Taupenot et al. 2003). Elevated circulating CgAlevels have been demonstrated in serum or plasma ofpatients with various NE tumors (NETs; Nobels et al.1997, Guignat et al. 2001, Tomassetti et al. 2001).

Previous studies reported different ranges of sensitivity

and specificity for circulating CgA, according to

histological characteristics of the tumor and to disease

spread. These parameters have been demonstrated to

depend also on themethod used for serumorplasmaCgA

determination and on the threshold considered as

pathologic (Schurmann et al. 1992, Stridsberg et al.

1995, Nobels et al. 1997, Baudin et al. 2001, Stivanello

et al. 2001, Tomassetti et al. 2001). In order to clarify this

Endocrine-Related Cancer (2007) 14 473–482

Endocrine-Related Cancer (2007) 14 473–4821351–0088/07/014–473 q 2007 Society for Endocrinology Printed in Great Britain

DOI:10.1677/ERC-07-0001Online version via http://www.endocrinology-journals.org

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CROMOGRANINA “A” –  Variabilità in relazione alla metodica impiegata –  Può essere elevata in neoplasie nonNET (Mammella, Rene, Prostata,

Epatocarcinoma, AdenoK Pancreatico, Colon, K Ovaio) –  Sovrapposizione fra soggetti sani e malati NET (non identificato un cut-off certo) –  Falsi positivi

–  Gravidanza  –  Gastrite  Cronica  Atrofica  –  Dopo  esercizio  fisico  –  Ipertensione  arteriosa  –  Insufficienza  renale  ed  Insufficienza  cardiaca  –  Mal.  Neurodegenera6ve  (M.  di  Parkinson)  –  Tra=amen2  farmacologici:  Inibitori  di  pompa  protonica  

-  Da utilizzare con cautela nella diagnosi di primo livello dei NET -  Livelli elevati possono essere indicativi di malattia metastatica -  Utile nel monitoraggio della terapia

Vinik A.I.; Pancreas (39); 6; 2010

•  Metodica RIA / IRMA abbastanza equivalenti •  estensione del tumore: sensibilità 60-100% nei NET metastatici e 29-50% nei NET localizzati; •  tipo e localizzazione del tumore: sensibilità 96% nei NET funzionanti e 75% nei non funzionanti.

Modlin et Al; Ann Surg Oncol 2010, 17: 2427-43 Campana D et Al; J Clin Oncol 2007, 25: 1967-73 Zatelli et Al; Svenja Nölting et Al.; Cancers 2012, 4, 141

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NSE

–  Positività in Carcinoma Tiroideo, Prostatico, Neuroblastoma, Microcitoma Polmonare, GEP e Feocromocitoma

–  Livelli elevati nel 30 – 50% dei pazienti con NET, specie se scarsamente differnziati

–  Sensibilità 100% ma specificità 33 % •  L’utilità clinica di questo marcatore è scarsa,

vista la bassa specificità. •  La sensibilità nella diagnostica dei NET può

essere aumentata dalla combinazione di NSE con CgA

Korse CM; Eur J Cancer 2012, 48 (5): 662–71. Vinik A.I.; Pancreas (39); 6; 2010

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In general, there was no association between CgA and NSEand the primary site, except for CgA in the SCNEC: sensitivity

(i.e. percentage of elevated values) in lung tumours was lowercompared to non-lung tumours (33% and 54%, respectively)(Table 2). In the poorly differentiated group, an associationwas found between primary site and proGRP: in the LCNECthe sensitivity in the tumours of the gastrointestinal tractwas 17% compared with 53% in the tumours of the non-gastrointestinal tract. In the SCNEC the sensitivity in the lungwas 76% compared with 54% in the non-lung tumours. Thesensitivity of the CKfr in the tumours of the gastrointestinaltract appeared to be higher than in the other tumours, butwas not statistically proven.

Within all histological groups the percentage elevated val-ues of all four markers were higher in patients with distantmetastases than in patients with locoregional disease.

3.1. Survival analyses

The Martingale residual plots indicate that in the well-differ-entiated group NSE and proGRP appeared to have approxi-mately the same thresholds as defined in the healthygroup as ULN (13.0 lg/l and 53 ng/l, respectively). Both CgAand CKfr appeared to be log-linearly related to overall sur-vival. In the univariate Cox regression analyses, sex, age,metastatic disease, primary site, grade of differentiation,and all four tumour markers were associated with overallsurvival (Table 3). In the multivariate model only age, meta-

static disease and CKfr were independently associated withoverall survival (P = 0.0004, P = 0.01 and P < 0.0001, respec-tively). Fig. 3A and B show the survival curves for CgA andCKfr divided by quartiles for patients with well-differentiatedNET.

P= .261 P<.001

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1000000

proG

RP

(ng/

l)

1

10

100

1000

10000

100000

Cyto

kera

tin fr

agm

ents

(U/l)

Healthy Healthy

Healthy Healthy

P<.001 P<.217

P<.001

P= .003 P<.001

P<.001

P<.001 P=.011

P<.001

Fig. 1 – Scatterplots of chromogranin A, neuron specific enolase (NSE), progastrin releasing peptide (proGRP) and cytokeratinfragments CK8, CK18 and CK19 in healthy persons, in patients with grade 1 and grade 2 neuroendocrine tumours (G1NET andG2NET, respectively), and in patients with large cell and small cell neuroendocrine tumours (LCNEC and SCNEC, respectively).Comparisons are made with Mann–Whitney tests. Dotted lines present the upper limit of normal.

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 6 6 2 – 6 7 1 665

1. Introduction

Classification of neuroendocrine tumours (NET) is an area ofongoing debate.32,33,39 In 2010, the WHO released a new clas-sification scheme for the digestive system based on histolog-ical grade.4 This classification divides NETs into well-differentiated NET, including grade 1 and 2 (G1NET andG2NET) and poorly differentiated (grade 3) neuroendocrinecarcinoma (NEC), including large and small cell neuroendo-crine carcinoma (LCNEC and SCNEC). Meanwhilst, the classi-fication for lung tumours has not changed since 1994 and was

already based on grade of differentiation.39 These tumoursare divided into typical (comparable to grade 1) and atypical(comparable to grade 2) carcinoid, based on the number ofmitoses per high-power field in combination with the pres-ence of necrosis.

Currently, chromogranin A (CgA) is the most frequentlyused marker, especially in the management of patients withwell-differentiated NET, but has some limitations, as variousassays are available and an international standardisation islacking. In addition, elevated CgA levels may be caused by re-nal or liver failure, and the use of proton pump inhibitors.13,22

For poorly differentiated NEC, neuron-specific enolase (NSE)is the marker of choice.8,9,29 NSE is present in neurons andneuroendocrine cells and can therefore serve as biomarker.Progastrin-releasing peptide (proGRP) is a promising tumourmarker for small cell lung cancer (SCLC).23,25 ProGRP is theprecursor of the neuropeptide gastrin-releasing peptide(GRP) and its production is increased in SCLCs.23,25 Molinaet al. described elevated levels in patients with NET, but thehistological characteristics of these tumours were not men-tioned. Cytokeratin fragments (CKfr) are sensitive indicatorsof tumour cell turnover and thus especially useful in the man-

agement of patients with malignancies of epithelial origin.3

MonoTotal! is an assay used to determine cytokeratin 8, 18and 19 (CK8, CK18 and CK19) fragments in serum. Moreover,CKfr is associated with angiogenesis factors which may playa role in NET; however, CKfr has not yet been investigatedin NET.5,10

Therefore, this study evaluates the role of CgA, NSE, proG-RP and CKfr in the diagnosis and prognosis of NET.

2. Patients and methods

2.1. Patients

Serum samples of all consecutive patients diagnosed withNETs from 1994 until 2009 were used for the present studywith their consent. From each patient one blood samplewas taken at the time of initial presentation to our institute.After centrifuging, serum was stored at )30 "C untilmeasurement.

Patients were divided into two main groups according to

the WHO classification4,16,38: well-differentiated NET (G1NETand G2NET); and poorly differentiated NEC (grade 3) withLCNEC and SCNEC. In addition, age, sex, survival data, stageof disease (limited/extensive in case of SCNEC, or locore-gional/metastasised in other histological groups), localisation

of the primary tumour and pretreatment (yes/no) wereregistered.

2.2. Healthy volunteers

Relatives of randomly chosen patients visiting our hospitalwere asked to donate blood for research, if they had no cancerin the past. Written informed consent was received.

2.3. Serum assays

CgA levels were measured by a solid-phase, two-site immuno-radiometric assay, the CGA-RIA kit (CIS Bio-international,

Gif-sur-Yvette, France) as described before.12,18,20 NSE levelswere measured with the Modular Analytics E170 (Elecsysmodule) analyser (Roche Diagnostics, Mannheim, Germany)using the electrochemiluminescence immunoassay (ECLIA)technique.27 ProGRP levels were measured with theARCHITECT immunoassay analyzer (Abbott, Wiesbaden,Germany). CKfr were determined by means of theMonoTotal#IRMA assay (IDL Biotech AB, Bromma, Sweden).CKfr measures defined epitopes of CK8, CK18 and CK19, usingthe monoclonal antibodies 6D7, 3F3 and IDLC4.5

2.4. Statistical analyses

Due to the asymmetric distribution of the biomarker valuesnatural log-transformations were applied. Upper limits ofnormal (ULN) for healthy persons were defined as the 95thpercentile according to the guidelines of the Clinical and Lab-oratory Standards Institute.15 The sensitivity of the tumourmarkers for the different histological groups was calculatedas the percentage of elevated levels according to the ULN. Dif-ferences in sensitivities between the primary sites or betweenthe stages of diseases were calculated with Fisher’s Exact

Tests. Receiver Operating Characteristic (ROC) curves wereconstructed to compare the predictive ability of the markersto discriminate the patients with NET of different histologicalgroups from healthy persons.14

Martingale residual plots were used to assess the appropri-ate functional form of the tumour markers in relation to over-all survival.37 Univariate and multivariate Cox proportionalhazard models were constructed to determine the associationbetween patient characteristics and tumour markers, withoverall survival. The multivariate analysis included the covar-iates sex, age, metastatic disease, pretreatment, site and

grade of differentiation. Additional stepwise analyses wereperformed to determine why different factors became non-significant in the presence of others. The Kaplan–Meier tech-nique was employed to depict the association between thetumour markers (divided into quartiles) and survival.

3. Results

For this study a total of 855 serum samples were collected: 282healthy persons, 280 well-differentiated NET and 293 poorlydifferentiated NEC (Table 1). Almost half of the patients(264/573 = 46%), were pretreated before referral to our

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 6 6 2 – 6 7 1 663

Choice of tumour markers in patients with neuroendocrinetumours is dependent on the histological grade. A markerstudy of Chromogranin A, Neuron specific enolase,Progastrin-releasing peptide and cytokeratin fragments

Catharina M. Korse a,*, Babs G. Taal b, Andrew Vincent d,Marie-Louise F. van Velthuysen c, Paul Baas b,Johanna C.G.M. Buning-Kager a, Theodora C. Linders a, Johannes M.G. Bonfrer a,d

a Department of Clinical Chemistry, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, P.O. Box 90203,1006 BE Amsterdam, The Netherlandsb Department of Medical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsc Department of Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsd Department of Biometrics, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

A R T I C L E I N F O

Article history:

Available online 22 September 2011

Keywords:

Neuroendocrine tumours

Chromogranin A

NSE

ProGRP

Cytokeratins

MonoTotal

A B S T R A C T

Background: Chromogranin A (CgA) is the most important tumour marker for well-differen-

tiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differen-

tiated neuroendocrine carcinoma (NEC). This study investigated whether the markers

progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and

CK19 (MonoTotal!) can be of additional value to the histological classification and help pre-

dict survival in these patients.

Methods: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET

(G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell

NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteris-

tics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox

regression analyses.

Results: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively)

when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP

showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivar-

iate survival analysis, only CKfr was associated with survival (P < 0.0001) for patients with

well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC,

both CKfr and NSE were associated with survival (P < 0.0001 and P = 0.003, respectively).

Conclusion: Within all histological groups a combination of tumour markers proved to be

more informative as diagnostic and prognostic marker than each marker alone. In patients

with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in

patients with SCNEC, proGRP and CKfr are preferred.

" 2011 Elsevier Ltd. All rights reserved.

0959-8049/$ - see front matter " 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.ejca.2011.08.012

* Corresponding author: Tel.: +31 20 5122794; fax: +31 20 5122799.E-mail address: [email protected] (C.M. Korse).

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 6 6 2 – 6 7 1

Avai lab le at www.sc iencedi rect .com

journal homepage: www.ejconl ine.com

Choice of tumour markers in patients with neuroendocrinetumours is dependent on the histological grade. A markerstudy of Chromogranin A, Neuron specific enolase,Progastrin-releasing peptide and cytokeratin fragments

Catharina M. Korse a,*, Babs G. Taal b, Andrew Vincent d,Marie-Louise F. van Velthuysen c, Paul Baas b,Johanna C.G.M. Buning-Kager a, Theodora C. Linders a, Johannes M.G. Bonfrer a,d

a Department of Clinical Chemistry, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, P.O. Box 90203,1006 BE Amsterdam, The Netherlandsb Department of Medical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsc Department of Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsd Department of Biometrics, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

A R T I C L E I N F O

Article history:

Available online 22 September 2011

Keywords:

Neuroendocrine tumours

Chromogranin A

NSE

ProGRP

Cytokeratins

MonoTotal

A B S T R A C T

Background: Chromogranin A (CgA) is the most important tumour marker for well-differen-

tiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differen-

tiated neuroendocrine carcinoma (NEC). This study investigated whether the markers

progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and

CK19 (MonoTotal!) can be of additional value to the histological classification and help pre-

dict survival in these patients.

Methods: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET

(G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell

NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteris-

tics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox

regression analyses.

Results: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively)

when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP

showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivar-

iate survival analysis, only CKfr was associated with survival (P < 0.0001) for patients with

well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC,

both CKfr and NSE were associated with survival (P < 0.0001 and P = 0.003, respectively).

Conclusion: Within all histological groups a combination of tumour markers proved to be

more informative as diagnostic and prognostic marker than each marker alone. In patients

with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in

patients with SCNEC, proGRP and CKfr are preferred.

" 2011 Elsevier Ltd. All rights reserved.

0959-8049/$ - see front matter " 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.ejca.2011.08.012

* Corresponding author: Tel.: +31 20 5122794; fax: +31 20 5122799.E-mail address: [email protected] (C.M. Korse).

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 6 6 2 – 6 7 1

Avai lab le at www.sc iencedi rect .com

journal homepage: www.ejconl ine.com

Choice of tumour markers in patients with neuroendocrinetumours is dependent on the histological grade. A markerstudy of Chromogranin A, Neuron specific enolase,Progastrin-releasing peptide and cytokeratin fragments

Catharina M. Korse a,*, Babs G. Taal b, Andrew Vincent d,Marie-Louise F. van Velthuysen c, Paul Baas b,Johanna C.G.M. Buning-Kager a, Theodora C. Linders a, Johannes M.G. Bonfrer a,d

a Department of Clinical Chemistry, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, P.O. Box 90203,1006 BE Amsterdam, The Netherlandsb Department of Medical Oncology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsc Department of Pathology, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlandsd Department of Biometrics, The Netherlands Cancer Institute – Antoni van Leeuwenhoek Hospital, Amsterdam, The Netherlands

A R T I C L E I N F O

Article history:

Available online 22 September 2011

Keywords:

Neuroendocrine tumours

Chromogranin A

NSE

ProGRP

Cytokeratins

MonoTotal

A B S T R A C T

Background: Chromogranin A (CgA) is the most important tumour marker for well-differen-

tiated neuroendocrine tumours (NET) and neuron specific enolase (NSE) for poorly differen-

tiated neuroendocrine carcinoma (NEC). This study investigated whether the markers

progastrin-releasing peptide (proGRP) and cytokeratin fragments (CKfr) CK8, CK18 and

CK19 (MonoTotal!) can be of additional value to the histological classification and help pre-

dict survival in these patients.

Methods: CgA, NSE, proGRP and CKfr were measured in 242 patients with grade 1 NET

(G1NET), 38 with grade 2 NET (G2NET), 42 with large cell NEC (LCNEC), 251 with small cell

NEC (SCNEC) and in 282 healthy persons. Results were compared with tumour characteris-

tics and survival by means of Receiver Operating Characteristics (ROC) curves and Cox

regression analyses.

Results: The largest area under the ROC curve was for CgA (0.86, 0.91 and 0.90, respectively)

when comparing patients with G1NET, G2NET and LCNEC with healthy persons. ProGRP

showed the highest sensitivity (73%) at 95% specificity in patients with SCNEC. In a multivar-

iate survival analysis, only CKfr was associated with survival (P < 0.0001) for patients with

well-differentiated NET (G1NET and G2NET). For patients with poorly differentiated NEC,

both CKfr and NSE were associated with survival (P < 0.0001 and P = 0.003, respectively).

Conclusion: Within all histological groups a combination of tumour markers proved to be

more informative as diagnostic and prognostic marker than each marker alone. In patients

with well-differentiated NET and LCNEC we recommend the use of CgA and CKfr, whilst in

patients with SCNEC, proGRP and CKfr are preferred.

" 2011 Elsevier Ltd. All rights reserved.

0959-8049/$ - see front matter " 2011 Elsevier Ltd. All rights reserved.doi:10.1016/j.ejca.2011.08.012

* Corresponding author: Tel.: +31 20 5122794; fax: +31 20 5122799.E-mail address: [email protected] (C.M. Korse).

E U R O P E A N J O U R N A L O F C A N C E R 4 8 ( 2 0 1 2 ) 6 6 2 – 6 7 1

Avai lab le at www.sc iencedi rect .com

journal homepage: www.ejconl ine.com

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Come arriva a noi il paziente ?

•  SINTOMI sospetti per una SINDROME

•  SINTOMI “ASPECIFICI”

•  RISCONTRO INCIDENTALE

•  QUALCUNO ha chiesto la determinazione della Cromogranina A…..

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occur many times per day; however, over many years, patientsmay develop a persistent flush with a purpuric malar and nasalcomplexion.

The differential diagnosis of flushing includes the post-menopausal state, simultaneous ingestion of chlorpropamideand alcohol, panic attacks, MCT, autoimmune epilepsy, auto-nomic neuropathy, and mastocytosis.5 To differentiate all thosecauses from a carcinoid tumor, besides knowing the differencesin the characteristics of the flushing, it is also necessary to knowwhat is producing the flushing (Table 3).

Flushing in carcinoid syndrome has been ascribed toprostaglandins, kinins, and serotonin (5-HT). With the advent ofsophisticated radioimmunoassay methods and region-specificantisera, a number of neurohumors now are thought to be se-creted by carcinoid tumors, including 5-HT, dopamine, hista-mine, and 5-hydroxyindoleacetic acid (5-HIAA), kallikrein,

substance P, neurotensin, motilin, somatostatin, vasoactive in-testinal polypeptide (VIP), prostaglandins, neuropeptide K, andgastrin-releasing peptide.

Several provocative tests have been developed to identifythe cause of flushing in carcinoid syndrome. These tests arebased on the need to distinguish the flushing from that found in ahost of other conditions particularly in panic syndrome in whichthe associate anxiety and phobias usually establish the cause, butfrequently, the physician and patient need reassurance that thereis no underlying malignancy.

Feldman and O’Dorisio6 have previously reported the inci-dence of elevated levels of plasma neuropeptide concentrationsin patients with flushing. Despite the elevated basal concentrationsof substance P and neurotensin, these authors were able to doc-ument further increases in these neuropeptides during ethanol-induced facial flushing.

TABLE 1. Clinical Presentations, Syndromes, Tumor Types, Sites, and Hormones4

Clinical Presentation Syndrome Tumor Type Sites Hormones

Flushing Carcinoid Carcinoid Midgut/foregut, adrenalmedulla, gastric

Serotonin, CGRP, calcitonin

Medullary carcinomaof thyroid

C cell tumor Metanephrine andnormetanephrine

pheochromocytoma Tumor of chromaffin cells Thyroid C cellsAdrenal and sympatheticnervous system

Diarrhea abdominalpain and dyspepsia

Carcinoid, WDHHAsyndrome, ZES,PP, MCT

Carcinoid, VIPoma,gastrinoma, PPoma,medullary carcinomathyroid, mastocytoma

As above, pancreas,mast cells, thyroid

As above, VIP, gastrin,PP, calcitonin

Diarrhea/steatorrhea Somatostatin,bleeding GI tract

Somatostatinoma,neurofibromatosis

Pancreas, duodenum Somatostatin

Wheezing Carcinoid Carcinoid Gut/pancreas/lung SP, CGRP, 5-HTUlcer/dyspepsia ZES Gastrinoma Pancreas/duodenum GastrinHypoglycemia Whipple triad Insulinoma, sarcoma,

hepatomaPancreas, retroperitonealliver

Insulin, IGF-1, IGF-11

Dermatitis Sweet syndrome,pellagra

Glucagonoma Pancreas Glucagon

Carcinoid Midgut SerotoninDementia Sweet syndrome Glucagonoma Pancreas GlucagonDiabetes Glucagonoma Glucagonoma Pancreas Glucagon

Somatostatin Somatostatinoma Pancreas SomatostatinDeep vein thrombosis,steatorrhea, cholelithiasis

Somatostatin Somatostatinoma Pancreas Somatostatin

neurofibromatosis DuodenumSilent, livermetastasis

Silent PPoma Pancreas PP

This table summarizes the suggested approach to diagnose a NET based on the clinical presentation, the tumor type, their sites of origin, and thepossible means of diagnosis and the biochemical markers that should be measured.

CGRP indicates calcitonin gene-related peptide; WDHHA, watery diarrhea, hypokalemia, hyperchlorhydria, and acidosi.

TABLE 2. Clinical Presentation, Syndrome, Tumor Type of Ectopic Pancreatic Tumors, and the Hormones Produced

Clinical Presentation Syndrome Tumor Type Sites Hormones

Acromegaly Acromegaly, Gigantism NET Pancreas islet GHRHCushing Cushing NET Pancreas islet CRH, ACTHPigmentation Pigmentation NET Pancreas islet Melanocyte-stimulating hormoneAnorexia, nausea, vomiting, abdominal pain Hypercalcemia NET Pancreas islet PTH-rP

Vinik et al Pancreas & Volume 39, Number 6, August 2010

714 www.pancreasjournal.com * 2010 Lippincott Williams & Wilkins

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

occur many times per day; however, over many years, patientsmay develop a persistent flush with a purpuric malar and nasalcomplexion.

The differential diagnosis of flushing includes the post-menopausal state, simultaneous ingestion of chlorpropamideand alcohol, panic attacks, MCT, autoimmune epilepsy, auto-nomic neuropathy, and mastocytosis.5 To differentiate all thosecauses from a carcinoid tumor, besides knowing the differencesin the characteristics of the flushing, it is also necessary to knowwhat is producing the flushing (Table 3).

Flushing in carcinoid syndrome has been ascribed toprostaglandins, kinins, and serotonin (5-HT). With the advent ofsophisticated radioimmunoassay methods and region-specificantisera, a number of neurohumors now are thought to be se-creted by carcinoid tumors, including 5-HT, dopamine, hista-mine, and 5-hydroxyindoleacetic acid (5-HIAA), kallikrein,

substance P, neurotensin, motilin, somatostatin, vasoactive in-testinal polypeptide (VIP), prostaglandins, neuropeptide K, andgastrin-releasing peptide.

Several provocative tests have been developed to identifythe cause of flushing in carcinoid syndrome. These tests arebased on the need to distinguish the flushing from that found in ahost of other conditions particularly in panic syndrome in whichthe associate anxiety and phobias usually establish the cause, butfrequently, the physician and patient need reassurance that thereis no underlying malignancy.

Feldman and O’Dorisio6 have previously reported the inci-dence of elevated levels of plasma neuropeptide concentrationsin patients with flushing. Despite the elevated basal concentrationsof substance P and neurotensin, these authors were able to doc-ument further increases in these neuropeptides during ethanol-induced facial flushing.

TABLE 1. Clinical Presentations, Syndromes, Tumor Types, Sites, and Hormones4

Clinical Presentation Syndrome Tumor Type Sites Hormones

Flushing Carcinoid Carcinoid Midgut/foregut, adrenalmedulla, gastric

Serotonin, CGRP, calcitonin

Medullary carcinomaof thyroid

C cell tumor Metanephrine andnormetanephrine

pheochromocytoma Tumor of chromaffin cells Thyroid C cellsAdrenal and sympatheticnervous system

Diarrhea abdominalpain and dyspepsia

Carcinoid, WDHHAsyndrome, ZES,PP, MCT

Carcinoid, VIPoma,gastrinoma, PPoma,medullary carcinomathyroid, mastocytoma

As above, pancreas,mast cells, thyroid

As above, VIP, gastrin,PP, calcitonin

Diarrhea/steatorrhea Somatostatin,bleeding GI tract

Somatostatinoma,neurofibromatosis

Pancreas, duodenum Somatostatin

Wheezing Carcinoid Carcinoid Gut/pancreas/lung SP, CGRP, 5-HTUlcer/dyspepsia ZES Gastrinoma Pancreas/duodenum GastrinHypoglycemia Whipple triad Insulinoma, sarcoma,

hepatomaPancreas, retroperitonealliver

Insulin, IGF-1, IGF-11

Dermatitis Sweet syndrome,pellagra

Glucagonoma Pancreas Glucagon

Carcinoid Midgut SerotoninDementia Sweet syndrome Glucagonoma Pancreas GlucagonDiabetes Glucagonoma Glucagonoma Pancreas Glucagon

Somatostatin Somatostatinoma Pancreas SomatostatinDeep vein thrombosis,steatorrhea, cholelithiasis

Somatostatin Somatostatinoma Pancreas Somatostatin

neurofibromatosis DuodenumSilent, livermetastasis

Silent PPoma Pancreas PP

This table summarizes the suggested approach to diagnose a NET based on the clinical presentation, the tumor type, their sites of origin, and thepossible means of diagnosis and the biochemical markers that should be measured.

CGRP indicates calcitonin gene-related peptide; WDHHA, watery diarrhea, hypokalemia, hyperchlorhydria, and acidosi.

TABLE 2. Clinical Presentation, Syndrome, Tumor Type of Ectopic Pancreatic Tumors, and the Hormones Produced

Clinical Presentation Syndrome Tumor Type Sites Hormones

Acromegaly Acromegaly, Gigantism NET Pancreas islet GHRHCushing Cushing NET Pancreas islet CRH, ACTHPigmentation Pigmentation NET Pancreas islet Melanocyte-stimulating hormoneAnorexia, nausea, vomiting, abdominal pain Hypercalcemia NET Pancreas islet PTH-rP

Vinik et al Pancreas & Volume 39, Number 6, August 2010

714 www.pancreasjournal.com * 2010 Lippincott Williams & Wilkins

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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•  5-HIIA (Sdr da Carcinoide) •  Gastrina (Sdr Zollinger – Ellison) •  Glucagone (Sdr di Becker) •  VIP (Sdr Vermer – Morrison) •  Insulina / C-Pep – test del digiuno (Insulinoma)

ALTRI MARKERS

Svenja Nölting et Al.; Cancers 2012, 4, 141

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Neurokinin ANeurokinin A has been shown to have a strong prognostic

value. Turner et al157 in 2006 showed that in patients with midgutcarcinoid that have raised plasma NKA, a reduction of thisbiochemical marker after somatostatin analog therapy was as-sociated with an 87% survival at 1 year compared with 40% ifit increased. They also concluded that any alteration in NKApredicts improved or worsening survival.157

DIAGNOSIS OF BONE METASTASISMetastases from NETs can be either lytic and/or osteo-

blastic (Table 4). There may be an increased osteoclast activitycontributing to lytic lesions and or an increased osteoblasticactivity responsible for blastic metastases. Bone markers inlytic and osteoblastic metastases that may assist in the evaluationof stage as well as response to therapy include bone alkalinephosphatase, an indicator of osteoblast function, and urinaryN-telopeptide, which reflects osteoclast activity or bone resorp-tion. Somewhat paradoxically, only blastic metastases show anincrease in both markers.158

Increased osteoclast activity predicts a poor outcome, witha relative risk (RR) for high N-telopeptide (9100 nmol BCE/mM

creatinine) of skeletal-related events, RR = 3.3 (P G 0.001);disease progression, RR = 2.0 (P G 0.001); and death, RR = 4.6(P G 0.001).159

BIOCHEMICAL DIAGNOSIS OFCARDIAC INVOLVEMENT

Carcinoid heart disease is a unique cardiac disease associ-ated with NETs and may be seen in up to 60% of patients withmetastatic carcinoid. Valvular disease is the most commonpathological feature, and tricuspid damage is found in 97% andpulmonary valve disease in 88%, with 88% displaying insuffi-ciency and 49% showing stenosis. The distinctive carcinoid le-sion consists of deposits of fibrous tissue devoid of elastic fibersknown as carcinoid plaque. The deposits are found on the en-docardial surface on the ventricular aspect of the tricuspid leafletand on the arterial aspect of the pulmonary valve cusps.160

Although the precise cause for the plaque formation is notentirely clear, the direct actions of 5-HT and bradykinin havebeen implicated in animal studies. This finding is corroboratedby the observation that the appetite-suppressant drug fenflur-amine, which releases 5-HT, has been noted to cause valvulardistortion similar to that seen in carcinoid heart disease.158

Values of 5-HT greater than 1000 ng/mL seem to consort withthe development of carcinoid heart disease.

ProYbrain natriuretic peptide can be used as a biomarkerfor the detection of carcinoid heart disease with high specificityand sensitivity and used as an adjunct to deciding who requiresechocardiography.159

INITIAL IMAGING OF THE PATIENTWITH A SUSPECTED NET

Imaging of Gastric Carcinoid TumorsMost gastric carcinoid tumors are directly imaged and di-

agnosed during endoscopy. For larger lesions, endoscopic ul-trasound (EUS) may be performed to assess whether the gastriccarcinoid is invasive. This technique, when used with tattooingof the gastric lesion, offers the endoscopist the opportunity toobserve the lesion in a serial fashion. This is highly valuablein the case of type I gastric carcinoids, which rarely need aformal gastric resection. In patients with more aggressive gastriccarcinoids such as type 2 gastric carcinoids, EUS offers theendoscopist the opportunity to access nearby nodes as well asthe depth of tumor invasion. Cross-sectional imaging with CTorMRI is recommended to assess for metastases in patients withtype I or type II gastric carcinoids more than 2 cm in diameter, orfor patients with type 3 gastric carcinoids in whom metastaticrisk is a concern.16 The predominant site of distant metastaticspread in patients with gastric carcinoid tumors is the liver. Carci-noid liver metastases are often hypervascular and may becomeisodense relative to the liver with the administration of intravenouscontrast. Computed tomography scans should thus be performedboth before and after the administration of intravenous contrastagents.163 Somatostatin receptor scintigraphy provides a seconduseful imaging modality for the detection of metastatic disease inpatients with malignant gastric carcinoids.16,163,164

Imaging of Midgut NETsImaging studies for NETs are generally done for initial

staging and subsequent follow-up. Goals for initial staging in-clude identification of primary tumor, assessment of extent ofdisease, and treatment planning. Subsequent follow-up imagingstudies are done for surveillance after complete resection orduring periods of stability and evaluation of response after

FIGURE 1. Algorithm for diagnosis of NETs.70Y72 Based on theclinical presentations, specific measures are selected for evaluationof each patient. NTx indicates N-telopeptide.

Vinik et al Pancreas & Volume 39, Number 6, August 2010

726 www.pancreasjournal.com * 2010 Lippincott Williams & Wilkins

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Vinik A.I.; Pancreas (39); 6; 2010

Tests conferma -  Secretina -  Calcio -  Digiuno

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Come arriva a noi il paziente ?

•  SINTOMI sospetti per una SINDROME

•  SINTOMI “ASPECIFICI”

•  RISCONTRO INCIDENTALE

•  QUALCUNO ha chiesto la determinazione della Cromogranina A…..

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•  Effetto massa della neoplasia •  Dolore addominale isolato (oppressivo – persistente, crampiforme) •  Sintomi occlusivi •  Emorragia digestiva •  Ittero

Paziente con sintomi aspecifici

Endoscopia digestiva Ecoendoscopia

ERCP Colonscopia

TAC ms/ RM Entero RM

VCE Ecografia con ctr

BIOPSIA / FNA / CHIR

DIAGNOSI

STAGING

(occlusione) Rx Addome

Chirurgia

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•  valido aiuto per la diagnosi dei GEP-NET o di eventuali metastasi presenti nel tratto gastroenterico.

•  richiedono agli operatori un training particolare •  vengono eseguite in sedazione. •  tecniche utilizzabili per la diagnosi dei NET:

•  Esofago-gastro-duodenoscopia (EGDS) •  Colonscopia •  EUS (ecoendoscopia) •  Videocapsula (ancora in studio) •  Broncoscopia

Tecniche Endoscopiche

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•  metodica principalmente usata per la valutazione delle dimensione della neoplasia, della profondità dell’infiltrazione e della presenza di linfonodi patologici;

•  molto utile nella diagnosi dei tumori NET pancreatici anche perché ci permette di effettuare esami citologici.

EUS

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•  TC MS: immagine di base •  RM: per i casi più problematici.

–  Nelle linee guida le due procedure vengono considerate equivalenti ed integrantesi a vicenda

•  La RM viene impiegata principalmente per la ricerca di: –  metastasi cerebrali –  caratterizzazione di lesioni epatiche e pancreatiche, specie se di piccole dimensioni –  masse nella piccola pelvi –  metastasi ossee

TAC o RM ?

Esito negativo sino al 50% dei casi Frilling A; Endocrine-Related Cancer (19); 163; 2012

Arterial phase CT Portal phase CT Hep.enhanced MRI

•  Entero-TC ed Entero-RM

Indicazione di scelta nel sospetto di NET del piccolo intestino

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•  metodica non invasiva, diffusa ed operatore-dipendente •  può essere utilizzata nei pazienti con basso BMI per la valutazione degli

organi parenchimatosi. •  La sua sensibilità può ridursi (13%-27%) nella definizione delle lesioni

pancreatiche per la presenza di gas intestinale. •  Tale metodica integrata con l’impiego di m.d.c. per via endovenosa viene

definita CEUS (contrast-enhanced ultrasound) aumenta l’accuratezza diagnostica.

•  valori di sensibilità analoghi tra CEUS e TC (83% e 95% rispettivamente) nell’identificazione di lesioni pancreatiche solide

•  bassa sensibilità dell’ecografia trans-addominale (circa 44%). •  può essere presa in considerazione in pazienti con allergia al m.d.c. o in

quelli affetti da insufficienza renale.

1386 Z. Fan et al. / European Journal of Radiology 82 (2013) 1385– 1390

the microcirculation of tissues and organs without penetrationinto the interstitial space. Meanwhile, the ultrasound technologyrealized real-time observation of tissue perfusion, providing morediagnostic information. The improvement of the diagnostic ratein pancreatic lesions by CEUS has been proven [3–5]. Studies byGrossjohann et al. showed that the diagnostic sensitivity of pan-creatic carcinoma by CEUS was as high as 85–90% [6–8]. In ourresearch, CEUS was employed in the diagnosis of 90 cases of solidpancreatic lesions, and a comparative study was carried out withCECT in the same period. The purpose was to explore the diagnosticvalue of CEUS for solid pancreatic lesions.

2. Materials and methods

2.1. Patients

Ninety patients with solid pancreatic lesions receiving bothCEUS and CECT examinations in our hospital from January 2009 toSeptember 2012 were selected, including 53 men and 37 women,ranging in age from 23 to 81 years, with the average age of 55.1years. The two examinations were carried out less than 1 monthapart. Sixty-six subjects underwent CA19-9 detection and 36 ofthem showed higher expression of the tumor marker.

Among the 90 patients, 58 were confirmed by surgical pathol-ogy, 12 were confirmed by biopsy and 20 by comprehensive clinicaldiagnosis. At least one of the following conditions should be met incomprehensive clinical diagnosis: (1) benign lesion confirmed bybiopsy with over 1 year of progression-free follow-up; (2) benignlesion confirmed by two methods among CT, MRI and PET-CTwith over 1 year of progression-free follow-up; (3) unresectablepancreatic carcinoma, with typical manifestations observed by pre-operative CT or MRI, that, upon intraoperative exploration, is foundto have invaded the surrounding tissues and vessels; (4) pancreaticmetastases confirmed by comprehensive clinical diagnosis includ-ing two methods among CT, MRI and PET-CT, clinical laboratory testand primary malignant tumor history.

2.2. US and CEUS

A GE Logiq 9 (GE Healthcare, Milwaukee, Wisconsin, USA) with aprobe frequency of 2.0–4.0 MHz and mechanical index of 0.08–0.10was used for the ultrasound examination. Lyophilized SonoVuepowder (Bracco Milan, Italy) was dissolved in 5 ml saline. Twomilliliters of the suspension was used for each examination andinjected via the antecubital vein within 2–3 s, followed by a 5 mlsaline flush.

US and CEUS were performed by an ultrasound physician withover 10 years of experience in pancreas. Patients were requiredto fast over 8 h before the examination. In the supine position,patients were first scanned with conventional US. The positions,sizes, boundaries, echoes and blood flows of the pancreatic lesionswere recorded. The patients were then scanned with CEUS. Thesurrounding pancreatic parenchymas were taken as a control. Real-time observation of the blood perfusion of the lesion should beno less than 120 s, during which the patients were instructed tomaintain smooth breathing. Dynamic images were preserved forlater analysis. Written informed consent was obtained from all thepatients before the examinations. No adverse reactions occurredafter CEUS.

The first 30 s of CEUS is defined as the early stage of enhance-ment, while 31–120 s is defined as the late stage. Taking thesurrounding pancreatic parenchyma as control, the enhancementand washout of the contrast agent in the lesions and surroundingparenchyma were observed. The enhancement of the lesion earlieror later than or equal to pancreatic parenchyma was defined as early

enhancement, late enhancement and equal enhancement, respec-tively. The washout was conducted similarly. The enhancementdegrees in lesions higher, lower than or equal to the surround-ing pancreatic parenchyma were defined as hyper-, hypo- or iso-enhancements, respectively. The highest enhancement degree wasdetermined if the lesion showed heterogeneous enhancement. Theenhancement of the largest lesion was determined if patients hadmultiple lesions.

Lesions were diagnosed separately by three ultrasound physi-cians with at least 5 years of CEUS experience without knowingin advance about the pathological or clinical diagnosis. US andCEUS images were analyzed and lesions were scored on a 5-pointscale: 1 = definitely benign, 2 = probably benign, 3 = undetermined,4 = probably malignant, 5 = definitely malignant. Any further spe-cific diagnosis made regarding the lesion was also recorded.Consensus was reached after discussion over any divergence. SeeTable 1 for the diagnostic criteria of CEUS [9,10].

2.3. Pancreatic CT plain scan + enhancement scan

GE Lightspeed 64-slice spiral CT scan was applied with a slicethickness of 5 mm, interlayer spacing of 5 mm, a pitch of 1.5 or 2 anda voltage of 120 kV. Ninety milliliters (300 mgI/ml) of the nonioniccontrast agent Iohexol was injected through the antecubital veinusing a high-pressure injector with an injection speed of 3.5 ml/s.The arterial phase scan started 25–30 s after the injection, followedby a venous phase scan 30–35 s later. CT images were read sepa-rately by two radiologists without knowing in advance about theCEUS results or pathological and clinical diagnosis. Consensus wasachieved after discussion over any divergence.

2.4. Statistical analysis

SPSS 13.0 software was employed for statistical analysis. TheX2 test was used for intergroup comparison. Interobserver agree-ment was assessed by weighted kappa statistics. The agreementwas graded as follows: no agreement (0), slight (0–0.20), fair(0.21–0.40), moderate (0.41–0.60), substantial (0.61–0.80) andperfect agreement (0.81–1). The diagnostic results of differentexaminations were recorded as sensitivity, specificity and accuracy,which were compared by the McNemar test. Receiver operatingcharacteristic (ROC) curves were plotted to evaluate the diagnosticperformance of CEUS and CECT in diagnosing pancreatic carcinomaand pancreatitis. p < 0.05 indicated statistical significance.

3. Results

3.1. Final diagnosis

Ninety subjects were enrolled, including 36 cases of pancreaticcarcinoma (31 confirmed by surgery, 3 by biopsy, 2 by clinical diag-nosis), 28 cases of pancreatitis (7 confirmed by surgery, 5 by biopsy,16 by clinical diagnosis), 6 cases of pancreatic neuroendocrinetumor (confirmed by surgery), 12 cases of solid pseudopapillarytumor (confirmed by surgery), 6 cases of pancreatic metastasis(1 confirmed by surgery, 4 by biopsy, 1 by clinical diagnosis; 4originated from lung cancer, 1 case of kidney cancer metasta-sis and 1 case of breast cancer metastasis), 1 case of cavernoushemolymphangioma (confirmed by surgery) and 1 case of lym-phoma (confirmed by clinical diagnosis).

3.2. Conventional US

Our study included 92 lesions of 90 patients with the maximumlesion diameter of 1.2–11.9 cm (mean 3.99 ± 1.89 cm). The lesionsof 55 cases were located on the head of the pancreas or uncinate

US ?

Z. Fan et al. / European Journal of Radiology 82 (2013) 1385– 1390 1389

Fig. 3. A 78 years old woman. (a) US shows a hypoechoic solid lesion in pancreatic head (T: tumor; P: pancreas). (b) The lesion enhances lately than that of the pancreas inthe early stage of CEUS (arrow). (c) The lesion is hypoechoic with respect to surrounding pancreas in the late stage of CEUS (arrow). (d) The lesion shows hypodense at CECT(arrow). (e) Pathologic diagnosis is moderately differentiated tubular adenocarcinoma (H and E, ×100).

mass-forming pancreatitis could be diagnosed accurately. The dif-ferentiation degree of pancreatic adenocarcinoma influences itsmicrovascular density. In cases of well-differentiated carcinomathe mass tends to be isovascular compared to the surroundingparenchyma [14,18]. All of the misdiagnosed cases in this studywere well to moderate differentiation. The lesions showed iso-enhancment in the early stage, which was possibly related to thedifferentiation degree and microvascular density.

Studies revealed that [17,19] the intensity of this “parenchymo-graphic” enhancement is related to the length of the underlyinginflammatory process. It has been observed that, the more chronicand long-standing the inflammatory process is, the less intenseis the intralesional “parenchymography”, probably in relation tothe entity of the associated fibrosis. On the contrary, in recent-onset mass-forming pancreatitis, the enhancement is usually moreintense and prolonged. Five pancreatitis cases in this study weremisdiagnosed as pancreatic adenocarcinoma because of hypo-enhancement in the early stage of enhancement. Therefore, for

these cases, combining disease history, CA19-9 results, and otherimaging examinations is helpful for diagnosis.

Although neuroendocrine tumors often show quick and obvioushyper-enhancement at the early stage in CEUS, some with no func-tion might show hypo-enhancement, depending on the amount ofstroma within the thick and hyalinized lesion [20]. Variable mani-festations in CEUS may affect the differential diagnosis. Among thesix cases of neuroendocrine tumor in this study, two cases showedhypo-enhancement at the early stage and were misdiagnosed aspancreatic adenocarcinoma.

Solid pseudopapillary tumor is a rare kind of pancreatic tumor.The parenchyma of the tumor is constituted by solid, pseudopap-illary and cystic area. The pathological characteristic of the tumoris pseudopapillary structure which present as the axis of fibrosisvessels surrounded by tumor cells [21,22]. This disease is morecommon in young women, and the manifestations in CEUS havenot been widely reported. Fan et al. [23] reported that capsulerim enhancement was mostly found at the early stage of CEUS.

Z. Fan et al. / European Journal of Radiology 82 (2013) 1385– 1390 1389

Fig. 3. A 78 years old woman. (a) US shows a hypoechoic solid lesion in pancreatic head (T: tumor; P: pancreas). (b) The lesion enhances lately than that of the pancreas inthe early stage of CEUS (arrow). (c) The lesion is hypoechoic with respect to surrounding pancreas in the late stage of CEUS (arrow). (d) The lesion shows hypodense at CECT(arrow). (e) Pathologic diagnosis is moderately differentiated tubular adenocarcinoma (H and E, ×100).

mass-forming pancreatitis could be diagnosed accurately. The dif-ferentiation degree of pancreatic adenocarcinoma influences itsmicrovascular density. In cases of well-differentiated carcinomathe mass tends to be isovascular compared to the surroundingparenchyma [14,18]. All of the misdiagnosed cases in this studywere well to moderate differentiation. The lesions showed iso-enhancment in the early stage, which was possibly related to thedifferentiation degree and microvascular density.

Studies revealed that [17,19] the intensity of this “parenchymo-graphic” enhancement is related to the length of the underlyinginflammatory process. It has been observed that, the more chronicand long-standing the inflammatory process is, the less intenseis the intralesional “parenchymography”, probably in relation tothe entity of the associated fibrosis. On the contrary, in recent-onset mass-forming pancreatitis, the enhancement is usually moreintense and prolonged. Five pancreatitis cases in this study weremisdiagnosed as pancreatic adenocarcinoma because of hypo-enhancement in the early stage of enhancement. Therefore, for

these cases, combining disease history, CA19-9 results, and otherimaging examinations is helpful for diagnosis.

Although neuroendocrine tumors often show quick and obvioushyper-enhancement at the early stage in CEUS, some with no func-tion might show hypo-enhancement, depending on the amount ofstroma within the thick and hyalinized lesion [20]. Variable mani-festations in CEUS may affect the differential diagnosis. Among thesix cases of neuroendocrine tumor in this study, two cases showedhypo-enhancement at the early stage and were misdiagnosed aspancreatic adenocarcinoma.

Solid pseudopapillary tumor is a rare kind of pancreatic tumor.The parenchyma of the tumor is constituted by solid, pseudopap-illary and cystic area. The pathological characteristic of the tumoris pseudopapillary structure which present as the axis of fibrosisvessels surrounded by tumor cells [21,22]. This disease is morecommon in young women, and the manifestations in CEUS havenot been widely reported. Fan et al. [23] reported that capsulerim enhancement was mostly found at the early stage of CEUS.

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Come arriva a noi il paziente ?

•  SINTOMI sospetti per una SINDROME

•  SINTOMI “ASPECIFICI”

•  RISCONTRO INCIDENTALE

•  QUALCUNO ha chiesto la determinazione della Cromogranina A…..

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•  La modalità più frequente di “presentazione” •  Riscontro Endoscopico •  Riscontro ECO / TAC / RM (metastasi epatiche / tumore pancreas)

Riscontro Incidentale

Endoscopia digestiva

BIOPSIA / FNA / CHIR

DIAGNOSI

STAGING

Sosp NET piccolo intestino

Sosp NET Gastroduodenale

TAC / RM EUS

Lesione ripetitiva Lesione pancreas

TAC / RM

BIOPSIA / FNA / CHIR

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•  Stadiazione morfologica

•  Stadiazione funzionale

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there are subtle differences between the concepts of differen-tiation and grade. Differentiation refers to the extent to which theneoplastic cells resemble their non-neoplastic counterparts. InNETs, well-differentiated examples have characteristic organoidarrangements of the tumor cells, with nesting, trabecular, orgyriform patterns. The cells are relatively uniform and produceabundant neurosecretory granules, reflected in the strong anddiffuse immunoexpression of neuroendocrine markers such aschromogranin A and synaptophysin. Poorly differentiated NETsless closely resemble non-neoplastic neuroendocrine cells andhave a more sheetlike or diffuse architecture, irregular nuclei,and less cytoplasmic granularity. Immunoexpression of neuro-endocrine markers is usually more limited. Grade, on the otherhand, refers to the inherent biologic aggressiveness of the tumor.Low-grade NETs are relatively indolent, high-grade tumors areextremely aggressive, and intermediate grade examples have aless predictable, moderately aggressive course. In general, well-differentiated NETs are either low or intermediate grade, andpoorly differentiated NETs are considered high grade in all cases(Table 2). The concept that some well-differentiated tumors couldnonetheless be biologically high grade has been proposed but iscontroversial.33

The systems of nomenclature reflect differentiation andgrading features of NETs. In essentially all systems, a sharpdivision is made between well-differentiated and poorly differ-entiated tumors, with the latter group being clearly designated ashigh-grade neuroendocrine carcinomas (neuroendocrine carci-noma, grade 3), including small-cell carcinoma and large-cellneuroendocrine carcinoma variants. Combined (mixed) forms

with elements of non-neuroendocrine carcinoma (usually adeno-carcinoma or squamous cell carcinoma) are also well recognized.The distinction of well-differentiated from poorly differentiatedNETs is probably one of the most important pathologic assess-ments related to these neoplasms, as the biologic behavior ofthe well-differentiated group is often rather indolent, whereaspoorly differentiated neuroendocrine carcinomas are very highlyaggressive; therapy also differs significantly between these 2categories of tumors. The term carcinoma also has been appliedto well-differentiated tumors, however. In some systems (par-ticularly the prior 2001 and 2004 versions of the WHO classi-fications of digestive and pancreatic NETs5,13,18), carcinomawas used in the place of tumor for neoplasms with obviousevidence of malignant behavior, such as vascular invasion, grosslocal invasion, or metastases. Others have argued to use the termcarcinoma for all NETs to specify that all are regarded to bemalignant.23 However, the use of the same term for all gradesof NETs implies a relationship between the well-differentiatedand poorly differentiated groups that does not exist in mostinstances. It is most important to recognize that the unqualifiedterms neuroendocrine carcinoma and neuroendocrine tumor,without reference to grade or differentiation, are inadequatefor prognostication or therapy and considered inappropriate inpathology reports.

Well-differentiated (low and intermediate grade) NETs havebeen variably termed carcinoid tumor (typical and atypical),neuroendocrine tumor (grade 1 and grade 2), or neuroendocrinecarcinoma (low grade and intermediate grade), among otheroptions. Table 3 displays a comparison of the various systems ofnomenclature currently in use for NETs, along with the organsystems most commonly using each system. Although the cri-teria that define each category do not perfectly match among thevarious systems, there are several common themes. Each systemrecognizes 3 grades. In each, the low and intermediate grades areclosely related, well differentiated, and distinguished largely byproliferative rate (or necrosis). Finally, each system generallyrecognizes that individual tumors rarely display hybrid well-differentiated and poorly differentiated features.

The issue of functionality of NETs also impacts onnomenclature. Functioning NETs are defined based on the

TABLE 3. Systems of Nomenclature for Neuroendocrine Tumors

Grade

Lung and Thymus GEP-NETs GEP-NETs Lung and Thymus Pancreas

(WHO)34 (ENETS)28,29 (WHO 2010)3 (Moran et al)23 (Hochwald et al)14

Low grade Carcinoid tumor Neuroendocrinetumor, grade 1 (G1)

Neuroendocrineneoplasm, grade 1

Neuroendocrinecarcinoma, grade 1

Well-differentiatedpancreatic endocrineneoplasm, low grade

Intermediategrade

Atypical carcinoidtumor

Neuroendocrinetumor, grade 2 (G2)

Neuroendocrineneoplasm, grade 2

Neuroendocrinecarcinoma, grade 2

Well-differentiatedpancreatic endocrineneoplasm,intermediate grade

High grade Small cell carcinoma Neuroendocrinecarcinoma, grade 3(G3), small cellcarcinoma

Neuroendocrinecarcinoma, grade 3,small cell carcinoma

Neuroendocrinecarcinoma, grade 3,small cell carcinoma

Poorly differentiatedpancreatic endocrinecarcinoma, smallcell carcinoma

Large cellneuroendocrinecarcinoma

Neuroendocrinecarcinoma grade 3(G3), large cellneuroendocrine

Neuroendocrinecarcinoma, grade 3,large cellneuroendocrinecarcinoma

Neuroendocrinecarcinoma, grade 3,large cellneuroendocrinecarcinoma

Poorly differentiatedpancreatic endocrinecarcinoma, largecell neuroendocrinecarcinoma

The grade of the tumor MUST be included in the pathology report, along with a reference to the specific grading system being used. Unqualifiedterms such as neuroendocrine tumor or neuroendocrine carcinoma without reference to grade do not provide adequate pathology information.

TABLE 2. Grade Versus Differentiation in NeuroendocrineTumors

Differentiation Grade

Well differentiated Low grade (ENETS G1)Intermediate grade (ENETS G2)

Poorly differentiated High grade (ENETS G3)

Pancreas & Volume 39, Number 6, August 2010 Pathologic Classification of Neuroendocrine Tumors

* 2010 Lippincott Williams & Wilkins www.pancreasjournal.com 709

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

Stratificazione del rischio

presence of clinical symptoms due to excess hormone secretionby the tumor and include functioning carcinoid tumors and avariety of other functioning NETs arising in the pancreas orelsewhere. Terms reflecting the clinical syndromes may beapplied to these NETs, such as insulinoma, glucagonoma, andgastrinoma, although the term carcinoid tumor is used fortumors with or without the carcinoid syndrome. Although thereare prognostic implications to some of the functional categories(eg, insulinomas are generally very indolent), the biologicbehavior of most functioning NETs is still defined by the gradeand stage of the tumor (although the clinical consequences ofthe hormone hypersecretion can be significant). Furthermore, thefunctional status of the tumor is defined by the clinical findings,not by the pathologic appearance or immunohistochemicalprofile. Thus, the pathologic diagnosis of functioning NETsshould be the same as for analogous nonfunctioning NETs of thesame anatomic site, with the descriptive functional designationappended to the diagnosis when there is knowledge of a clinicalsyndrome.

GRADING ISSUESThe proliferative rate has been repeatedly shown to provide

significant prognostic information for NETs,2,12,16,19,24,26,35 andmost systems of grading rely extensively on the proliferative rateto separate low-, intermediate-, and high-grade tumors. Somesystems (such as the WHO classification for lung and thymus)include the presence of necrosis as a feature to distinguishintermediate grade from low grade within the well-differentiatedgroup.34 The proliferative rate can be assessed as the number ofmitoses per unit area of tumor (usually expressed as mitoses per10 high-power microscopic fields or per 2 mm2) or as the per-centage of neoplastic cells immunolabeling for the proliferationmarker Ki67.28,29 The WHO classification of lung and thymustumors relies only on the mitotic rate,34 whereas the systemrecently proposed for gastroenteropancreatic NETs by theEuropean Neuroendocrine Tumor Society (ENETS) and alsonow recommended by the WHO uses either mitotic rate or Ki67labeling index.3,29 A comparison of the most widely used gradingsystems is shown in Table 4. As can be seen, the cut-points todistinguish the 3 grades vary somewhat among the differentsystems, and definitive clinical data to determine the optimal cut-points do not exist. In fact, some studies suggest that the optimalcut-points may differ between organ systems.9,11,12,14 For thesereasons, it is recommended to specify the actual proliferative ratein the pathology report, in addition to designating a grade basedon a system that is specifically referenced.

The use of mitotic counts versus Ki67 index is controver-sial. In Europe, where the ENETS system is already in wide-spread use, Ki67 labeling indices are commonly reported for all

NETs. When the amount of tumor tissue is limited (eg, in abiopsy from a primary tumor or a metastatic focus), it may not bepossible to perform an accurate mitotic count because it isrecommended to count 40 to 50 high-power fieldsVmore thanmost biopsy samples contain. In these cases, Ki67 stainingprovides a more accurate assessment of proliferative rate, andit is particularly helpful to separate well-differentiated (low orintermediate grade) tumors from poorly differentiated (highgrade) neuroendocrine carcinomas, which usually have dra-matically different Ki67 labeling rates.7,20,27 However, whenadequate tissue is present to perform an accurate mitotic count,there are no data to demonstrate that the Ki67 labeling indexadds important additional information, and in some cases, the 2measures of proliferative rate may provide conflicting informa-tion about grading.

STAGING ISSUESA few years ago, no formal TNM-based staging systems

existed for NETs. Data submitted to the Surveillance, Epide-miology, and End Results (SEER) program of the NationalCancer Institute separated tumors into localized, regional, anddistant stages based on the presence of lymph node or distantmetastases, but substratification of the extent of the primarytumor was not performed.40 Recently, TNM staging systemshave been proposed. The American Joint Committee on Cancerhas recently published a new TNM staging manual that includesNETs of all anatomic sites,10 and the ENETS has previouslypublished recommendations for TNM staging of gastroentero-pancreatic NETs.25,28,29 There are some differences betweenthese systems, particularly for primary tumors of the pancreasand the appendix, but there is also considerable overlap. Addi-tionally, the staging criteria for both systems rely predominantlyon the size of the tumor and the extent of invasion into similarlandmarks as used for the staging of non-neuroendocrine car-cinomas of the same sites. It is recommended that the extent ofinvolvement of these structures be specifically indicated in thepathology reports in addition to providing a TNM stage using asystem that is specifically referenced.

Until very recently, the WHO classifications for NETs ofthe tubular gastrointestinal tract (2000) and pancreas (2004) useda hybrid classification system that incorporated both staginginformation (size and extent of tumorVlimited to the primarysite versus having metastases) and grading information (prolif-erative rate) into a single prognostic prediction system, with adifferent name being applied to the tumors in each prognosticgroup.4Y6,13 Although this system did allow prognostic stratifi-cation of NETs, it did not allow for grading information to beapplied to advanced stages of disease, preventing prognostica-tion once metastases occurred and therefore limiting information

TABLE 4. Grading Systems for Neuroendocrine Tumors

Grade

Lung and Thymus GEP-NETs Lung and Thymus Pancreas

(WHO)34 (ENETS, WHO)3,28,29 (Moran et al)23 (Hochwald et al)14

Low grade G2 mitoses / 10 hpfAND no necrosis

G2 mitoses / 10 hpfAND G3% Ki67 index

e3 mitoses / 10 hpfAND no necrosis

G2 mitoses / 50 hpfAND no necrosis

Intermediate grade 2Y10 mitoses / 10 hpfOR foci of necrosis

2Y20 mitoses / 10 hpfOR 3%Y20% Ki67 index

4Y10 mitoses / 10 hpfOR foci of necrosis

2Y50 mitoses / 50 hpfOR foci of necrosis

High grade 910 mitoses / 10 hpf 920 mitoses / 10 hpfOR 920% Ki67 index

910 mitoses / 10 hpf,Necrosis present

950 mitoses / 50 hpf

In the pathology report, the actual proliferative rate (mitotic count and/or Ki67 index) should be specified, and a grade should be provided, with thespecific grading system used to be specified in the report.

Klimstra et al Pancreas & Volume 39, Number 6, August 2010

710 www.pancreasjournal.com * 2010 Lippincott Williams & Wilkins

Copyright © 2010 Lippincott Williams & Wilkins. Unauthorized reproduction of this article is prohibited.

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Grading NETs •  Maria, di anni 65 alla diagnosi •  Nel Gennaio 2008, per addominalgie, esegue ECO ADDOME con riscontro di

Neoformazione della testa del Pancreas (Octreoscan positiva) e stadiazione negativa per cui viene sottoposta a DCP + Colecistectomia

•  ISTOLOGIA: neoplasia endocrina del Pancreas, 35 mm, T2, N0, M0; Ki67 2-4%, stadio II (Rindi 2006) ! WHO 2010 ! NET G2

•  Nel 2010: unico secondarismo epatico ! RFTA •  Nel 2011: ulteriori secondarismi epatici octreoscan positivi ! PRRT (90YDotatate) •  Nel 2012 – 2013: malattia stabile •  Nel 2014:

Per gentile concessione della Dr.ssa Letizia Boninsegna

Tutti i NET sono

caratterizzati da un rischio potenziale di progressione

di malattia

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ISRN Oncology 5

0 100 200 3000

20

40

60

80

100

Stage 2Stage 3Stage 4

Months from diagnosis

Surv

ival

(%)

(a)

0 50 1000

20

40

60

80

100

G1 SBNETG2 SBNET

Months from diagnosis

Surv

ival

(%)

(b)

Figure 2: (a) Cumulative small bowel NET survival according to TNM staging. Stage 2 versus stage 3 ! > 0.05 (nonsignificant), stage 2 +stage 3 versus stage 4 (! < 0.05), stage 3 versus stage 4 (! < 0.05). (b) Cumulative small bowel NET survival curve assessing histologicalgrade. G1 small bowel NETs had significantly better prognosis than G2 NETs (undefined versus 69months, ! < 0.05).Table 4: Cause of death in patients with small bowel neuroen-docrine tumours.

Cause of death Number of patients % of all deathsTumour burden 21 47.7Small bowel obstruction 6 13.6Intervention related (30 day) 2 4.5Carcinoid heart disease 5 11.4Tumour unrelated cause 9 20.5Unknown 1 2.7Total 44 100

survival for patients with stage 4 disease was 98months, with5-year survival of 74.5%.

Therewere 44 (32.8%) deaths during the follow-up periodof the study. The cause of death is displayed in Table 4.20.5% of patients died from nontumour-related deaths; themost common causes were cardiovascular death and a secondmalignancy.The cause of death could not be identified in onecase.

4. Discussion

We have demonstrated that the ENETS TNM staging systemfor midgut offers prognostic information, with the worst sur-vival demonstrated in patients with stage 4 disease comparedwith stage 2 or stage 3 disease. Furthermore, the proposedgrading system based on Ki67 and mitotic index providedstatistically different prognosis between G1 and G2 NETs.

Nodifference in survival was demonstrated between stage2 and stage 3 disease; this could be in part due to the durationof followup and small numbers of cases with stage 2 disease.However, other studies have not demonstrated difference insurvival between stage 2 and stage 3 disease [13]. Markers

of cellular proliferation as measured by Ki67 index andmitotic rate were incorporated in to the novel ENETS TNMstaging and grading system. Studies demonstrated thesemarkers as predictors of survival in pancreatic and uppergastrointestinal NETs and hence their incorporation into theENETs guidance [11, 22, 23]. In this study we demonstratedsignificant improvement in survival for patients with G1compared to those with G2 NETs; this supports the findingsin other studies [14, 24].

Overall the 5-year and 10-year survivals were 79.5% and48.5%, respectively, for all patients independent of stageof disease. This shows improvement in the 5-year survivalwhen compared to previous studies, including the SEERdata [6]. There appears to be a trend towards improvementin survival when looking at the 5-year survival data fromrecently published data looking at patient cohorts over thelast two decades [6, 12, 14]. The causes for this improvedsurvival have not been fully elucidated. It may be in partrelated to increased use of somatostatin analogues and theirantiproliferative effect. Secondly, the management of patientsin multidisciplinary teams and the more aggressive surgicalmanagement of these patients may have improved survival.The study cohort may be biased as it is not a population-based survival but instead a survival of patients managed in aspecialist centre. Finally, lead time bias may also be a factor;however, there is no clear evidence to support that patientsare being diagnosed at an earlier stage of the disease.

The cause of death in this study demonstrated that 47.3%were related to tumour progression which is similar to thatpublished in the UKINETs study [14]. A similar percentageof patients died from carcinoid heart disease and smallbowel obstruction [14, 25–27]. Interestingly 20.5% of patientsdied from tumour-unrelated causes, which is similar to thatidentified from previous studies [14, 28]; in part it could berelated to the longer survival of patients with small bowel

Staging: TNM NETs •  Nel 2010 la nuova classificazione AJCC include anche i NET

•  Sistema “misto”: per alcune sedi anatomiche è analoga ai tumori esocrini e per altre è specifica dei NET

•  Classificazione non univoca fra WHO ed ENETS, specie per Pancreas e Appendice; delle due, la classificazione ENETS sembra meglio correlare con la prognosi

STAGING

The prognostic importance of tumor stage is one ofthe more universal aspects of cancer biology, yet curi-ously, there were no specific tumor-node-metastasis(TNM) staging systems for NETs until very re-cently.14,15,19,69 A relatively crude staging system hasbeen used for years in the Surveillance, Epidemiologyand End Results (SEER) Program of the National CancerInstitute, which categorizes the extent of disease as“localized,” “regional” or “distant.”70 But no TNM sys-tem was developed for NETs until the ENETS gradingproposals for gastrointestinal and pancreatic NETs,published in 2006 and 2007, included a staging systemfor the primary tumors based on landmarks roughlyparalleling the systems previously in place for exocrinecarcinomas of the same organs.15,19 The prior WHOclassifications of 2000 and 2004 also included stagingparameters, but they were combined with grading pa-rameters into a single prognostic system.2–5 Finally in2010, the new edition of the AJCC staging manualincluded staging parameters for NETs of all anatomiclocations.14 For some sites, the criteria for staging arethe same as for exocrine carcinomas of those organs;for other sites, a unique system was developed specificto NETs. With the adoption of TNM staging, it shouldbe much easier to compare the extent of disease be-tween patients.

Unfortunately, the staging systems of the ENETS andthe WHO are not identical. The differences for someanatomic sites are rather trivial, but for the pancreasand the appendix, there are more substantive differ-

ences (Table 3).71 Although pathologists in the UnitedStates are often required to use the AJCC system byaccrediting agencies, early comparative data suggestthat the ENETS system more accurately stratifies prog-nosis.72,73 Updates of the AJCC system may take someof these studies into consideration, and modificationsare possible. Thus, it is important to collect the basicdata underlying all of the different staging systems inthe pathology reports. For gastroenteropancreaticNETs, the size of the primary tumor (in three dimen-sions) and the extent of invasion through the bowelwall or pancreas should be recorded, using the samelandmarks as for exocrine carcinomas of the same or-gans.14 In the lung, tumor size, extent of bronchial andpleura involvement, and invasion of extrapulmonarystructures should also be documented.14 The size of thelargest resected metastasis should be documented,along with the total number of metastases and the totalnumber of involved lymph nodes.13 The specific overallstage should be reported, and the system used to defineit should also be referenced.

One issue that has not been addressed is how tosubstage metastatic disease. For carcinomas, distantmetastases (stage IV for almost every tumor type) usu-ally equate to a uniformly dismal prognosis, so it hasnot proven necessary to subdivide stage IV cases inmost instances. For well-differentiated NETs, however,long-term survival is not uncommon for patients with alimited volume of metastatic disease. It is likely that theprognosis of a patient with a solitary, small liver metas-tasis will be much better than that of a patient with

Table 3. Comparison of the Criteria for the Tumor Category in the ENETS and Seventh Edition AJCCTNM Classifications of Pancreatic and Appendiceal NETs

ENETS TNM AJCC/UICC TNM

Pancreatic NETsT1 Confined to pancreas, !2 cm Confined to pancreas, !2 cmT2 Confined to pancreas, 2–4 cm Confined to pancreas, "2 cmT3 Confined to pancreas, "4 cm, or

invasion of duodenum or bile ductPeripancreatic spread, but without major

vascular invasion (Truncus coeliacus, A.mesent. sup.)

T4 Invasion of adjacent organs or majorvessels

Major vascular invasion

Appendiceal NETsT1 !1 cm; invasion of muscularis propria T1a, !1 cm; T1b, "1–2 cmT2 !2 cm and !3 mm invasion of

subserosa/mesoappendix"2–4 cm or invasion of cecum

T3 "2 cm or "3 mm invasion ofsubserosa/mesoappendix

"4 cm or invasion of ileum

T4 Invasion of peritoneum/other organs Invasion of peritoneum/other organsFrom Kloppel et al.71

Abbreviations: ENETS, European Neuroendocrine Tumor Society; TNM, tumor-node-metastasis; AJCC, American Joint Committee onCancer; UICC, International Union Against Cancer.

28 D.S. Klimstra

Hindawi Publishing CorporationISRN OncologyVolume 2013, Article ID 420795, 7 pageshttp://dx.doi.org/10.1155/2013/420795

Research ArticleENETS TNM Staging Predicts Prognosis in Small BowelNeuroendocrine Tumours

Rajaventhan Srirajaskanthan,1,2 A. Ahmed,1 A. Prachialias,1 P. Srinivasan,1 N. Heaton,1

N. Jervis,1 A. Quaglia,1 G. Vivian,3 and J. K. Ramage1,4

1 Institute of Liver Studies, King’s College Hospital, London SE5 9RS, UK2Department of Gastroenterology, University Hospital Lewisham, London SE13 6LH, UK3Nuclear Medicine, King’s College Hospital, London SE5 9RS, UK4Department of Gastroenterology, Basingstoke and North Hampshire Foundation Trust, Hampshire R924 9NA, UK

Correspondence should be addressed to Rajaventhan Srirajaskanthan; [email protected]

Received 20 December 2012; Accepted 11 January 2013

Academic Editors: J. Nylandsted and K. van Golen

Copyright © 2013 Rajaventhan Srirajaskanthan et al. This is an open access article distributed under the Creative CommonsAttribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work isproperly cited.

Introduction. Small bowel neuroendocrine tumours (NETs) are the most common type of gastrointestinal neuroendocrinetumours. The incidence and prevalence of these tumours are on the rise. The aims of this study were to determine prognosticclinicopathological features and whether the ENETS TNM staging system predicts prognosis and also. Method. Clinical datawas collected retrospectively from 138 patients with histologically proven small bowel NETs managed at King’s College Hospital.Histology was reviewed and small bowels tumours, were staged according to the ENETS TNM staging system. Results. Median agewas 65 years (range 29–87). The 5-year survival was 79.5% and the 10-year survival was 48.5%. Resection of the primary tumourwas associated with improved survival (120 versus 56months, ! < 0.05). On multivariate analysis prognostic factors were primarytumour resection and not having a carcinoid heart disease. TNM staging significantly separated survival of stage 2 and stage 3 fromstage 4NETs.Conclusion. Small bowel primary tumour resection and not having carcinoid heart disease are prognostic factors.TheENETS TNM staging and grading system appears to be of prognostic relevance to small bowel NETs.

1. Introduction

Neuroendocrine tumours of the small bowel are the mostcommon type of malignant neoplasm in the small intes-tine, accounting for 35% of small intestinal cancers [1, 2].Small bowel neuroendocrine tumours (NETs) are the mostcommon type of gastrointestinal neuroendocrine tumours[3]. Small bowel NETs comprise around 38% of gastroen-teropancreatic NETs and 21% of all NETs.The incidence andprevalence of these tumours are on the rise, as demonstratedin the Surveillance Epidemiology and End Results (SEER)data and the population-based study in Norway [2, 4]. Athreefold increase in incidence has been demonstrated inthe USA between 1973 and 2002 [5]. The reported incidenceof small bowel NETs is 1/100 000 population [6]. Themajority of these tumours do not cause carcinoid syndrome,often presenting late with metastatic disease. Patients with

non-hormone secreting tumours often present with vaguesymptoms, including intermittent abdominal pain or weightloss. A number of patients are identified coincidentally.Approximately 40% of patients with metastatic disease atpresentation have functionally active tumours leading to thedevelopment of carcinoid syndrome [7–10].

Small bowel NETs were generally thought to be indolenttumours; however, their behaviour is more heterogeneous,and consequently a staging and grading system has beenintroduced by European Neuroendocrine Tumour Society(ENETS) to help clinicians to optimize the management ofthese patients [11]. The ENETS grading system incorporatesKi67 index and mitotic rate to grade tumours; these parame-ters had not previously been incorporated to the WHO 2000classification of NETs.

Yao et al. demonstrated a median survival from presenta-tion of 65months for patients with stage 4 (distantmetastatic)

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Classification and tumor biology of NETs: differences between European and US staging of PNETs

Rindi  et  al.  J  Natl  Cancer  Inst  2012;  104:  1-­‐14  

Distribu2on  of  sub-­‐groups  survival  in  PNETs    

according  to  the  classifica2on  system  

ENETS  staging  be=er  correlates    

with  overall  survival    

than  UICC  (US)  staging  for  PNETs  

ESMO  Congress,  Vienna  se^embre  2012  

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•  Stadiazione morfologica

•  Stadiazione funzionale

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STADIAZIONE “FUNZIONALE”

•  fino all’80% dei NET esprime i recettori SSTR2 (in misura minore anche SSTR5) •  111In-pentetreotide (Octreoscan®) •  Metodiche PET (68-GallioDotanoc / Dotatoc / DotaTate)

•  Prima dell’avvento di queste tecniche in circa la metà dei casi non si riusciva ad identificare le neoplasia di origine

•  non dà informazioni sul grado di differenziazione o sulla secrezione ormonale specifica del tumore

•  OBIETTIVI •  localizzazione del tumore primitivo •  la stadiazione e la caratterizzazione delle lesioni tumorali

•  in termini di espressione di SSTR •  di metabolismo delle neuroamine e di consumo di glucosio

•  la ri-stadiazione della malattia durante e dopo i trattamenti. •  fattore predittivo di risposta per gli analoghi radiomarcati della somatostatina

(PRRT, peptide receptor radionuclide therapy).

•  L’imaging recettoriale mediante SRS o PET con 68Ga-peptidi è considerato ad oggi lo standard of care nella gestione delle GEP-NEN

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Octreoscan® SPECT / SSTR PET PET-FDG

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Take home message •  Non sottovalutare la sintomatologia aspecifica (dolori addominali, crisi di

sudorazione, alterazioni dell’alvo) specie se persistente nel tempo: attenzione all’anamnesi e all’obiettività (lesioni cutanee, pigmentazione..)

•  Nel sospetto clinico di un NET l’impiego dei marcatori aspecifici, CgA e NSE, va usato con prudenza tenendo presente che non sono da considerare adatti per uno screening e sono gravati da falsi positivi; possono essere impiegati in prima linea se il sospetto diagnostico è molto forte ma soprattutto, anche in associazione, per il follow – up terapeutico

•  La ricerca ormonale specifica va applicata in presenza di sintomi evocativi di una sindrome e devono comunque essere sempre associati alle valutazioni strumentali

•  Un adeguato approccio terapeutico presuppone una corretta stadiazione secondo criteri istologici, immunocitochimici, diffusione della malattia e comportamento all’imaging Medico Nucleare

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L’adeguato approccio diagnostico ai NET va discusso nell’ambito di un Team multidisciplinare (Endocrinologo, Chirurgo, Anatomo-Patologo, Medico Nucleare, Radiologo, Oncologo, Radioterapista e Psicologo dedicati)

Take home message

Un lavoro di squadra !

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Grazie per l’attenzione